Asthma is a major public health problem and the most common cause of chronic childhood disease in the United States, where it is usually associated with allergy. Gender differences in asthma prevalence that vary by stage-of-life are found in large cross-sectional national surveys, but longitudinal supporting evidence is sparse. In early childhood asthma is more common in young boys, but by adulthood females have higher asthma rates. Thus the preadolescent and adolescent years may be as influential as gestation and infancy in the sex-specific evolution of allergy and asthma. Sex differences in asthma and allergy development may be influenced both by gender differences in levels of environmental exposures, as well as by sex differences in responses to exposures. Two groups of exposures potentially contributing to sexual dimorphism in asthma and allergy are commensal bacteria and overweight, along with correlated behaviors and co-exposures. While the final common pathway for airflow obstruction includes airway narrowing and inflammation, murine studies suggest sex-specific differences in airway anatomy and in pathways leading to inflammation. Airway inflammation in humans with asthma has been shown to be less responsive to steroid treatment in females than in males. The relative contribution of biology (sex) vs behavior (gender) to life-cycle-specific female:male differences in asthma and allergy is poorly understood. We have published evidence for sex-linkage for allergic sensitization and, in an asthmatic population, have preliminary evidence for sexual dimorphism in gene expression. Taking advantage of 16 years of longitudinal data from a U.S. birth cohort with parental history of allergy or asthma, we hypothesize that: (1) Whereas boys will have higher rates of wheeze, active asthma, and allergy before adolescence, by age 16, girls will develop higher rates of wheeze, active asthma, and secondary phenotypes of airway inflammation (exhaled NO), airflow obstruction, and allergic sensitization. (2) Life-cycle-specific gender differences in wheeze, asthma, and secondary phenotypes linked to asthma will be partially explained by differential levels of exposure or by differential responses to commensal gram [unreadable] and gram + bacterial flora (e.g. endotoxin and peptidoglycan), increased body-mass index (BMI), along with correlated behaviors and coexposures (pets, home dampness for bacteria;low physical activity, vitamin D, and stress for BMI);(3) We will detect female:male biologic differences in peripheral blood mononuclear cell (PBMC) gene expression associated with allergic sensitization and airway inflammation at age 16. We will identify a set of differentially expressed genes that will be shared by boys and girls, as well as a second set of differentially expressed genes predicting allergic sensitization or airway inflammation that will be sex-specific, and may be in pathways influenced by commensal bacteria, body-mass index, and correlated co-exposures. This proposal is timesensitive, as the end of our current grant cycle coincides with completion of the first half, but not the second half of age 16 specimen collection for measurement of allergy, airway inflammation, and gene expression.